Abstract
Scatter factor (SF) [aka. hepatocyte growth factor (HGF)] (designated HGF/SF) is a multifunctional cytokine that stimulates tumor cell invasion and angiogenesis. We recently reported that HGF/SF protects epithelial and carcinoma cells against cytotoxicity from DNA-damaging agents and that HGF/SF-mediated cytoprotection was associated with up-regulation of the anti-apoptotic protein Bcl-X(L) in cells exposed to adriamycin. We now report that in addition to blocking apoptosis, HGF/SF markedly enhances the repair of DNA strand breaks caused by adriamycin or gamma radiation. Constitutive expression of Bcl-X(L) in MDA-MB-453 breast cancer cells not only simulated the HGF/SF-mediated chemoradioresistance, but also enhanced the repair of DNA strand breaks. The ability of HGF/SF to induce both chemoresistance and DNA repair was inhibited by wortmannin, suggesting that these activities of HGF/SF are due, in part, to a phosphatidylinositol-3'-kinase (PI3K) dependent signaling pathway. Consistent with this finding, HGF/SF induced the phosphorylation of c-Akt (protein kinase-B), a PI3K substrate implicated in apoptosis inhibition; and an expression vector encoding a dominant negative kinase inactive Akt partially but significantly inhibited HCF/SF-mediated cell protection and DNA repair. These findings suggest that HGF/SF activates a cell survival and DNA repair pathway that involves signaling through PI3K and c-Akt and stabilization of the expression of Bcl-X(L); and they implicate Bcl-X(L) in the DNA repair process.
Original language | English (US) |
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Pages (from-to) | 2212-2223 |
Number of pages | 12 |
Journal | Oncogene |
Volume | 19 |
Issue number | 18 |
DOIs | |
State | Published - Apr 27 2000 |
Keywords
- Adriamycin (doxorubicin)
- Breast cancer
- HGF/SF
- Hepatocyte growth factor (HGF)
- Scatter factor (SF)
- c-Met
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research